A core domain set for pyoderma gangrenosum trial outcomes: an international eDelphi and consensus study from the UPGRADE initiative.

BACKGROUND: Pyoderma gangrenosum (PG) is a rare ulcerative skin condition with no current standardized outcomes or outcome measures. With a rich investigational therapeutic pipeline, standardization of outcomes and improvement of data quality and interpretability will promote the appropriate and consistent evaluation of potential new therapies. Core outcome sets (COS) are agreed, standardized sets of outcomes that represent the minimum that should be measured and reported in all clinical trials of a specific condition. OBJECTIVES: To identify and reach a consensus on which domains (what to be measured) should be included in the Understanding Pyoderma Gangrenosum: Review and Analysis of Disease Effects (UPGRADE) core domain set for clinical trials in PG. METHODS: Collaborative discussions between patients and PG experts, and a systematic review of the literature identified items and prospective domains. A three-round international eDelphi exercise was performed to prioritize the domains and refine the provisional items (consensus: ≥ 70% of participants rating a domain as 'extremely important' and < 15% of participants voting 'not important'), followed by an international meeting to reach consensus on the core domain set (consensus: < 30% disagreement). Item-generation discussions and consensus meetings were hosted via online videoconferences. The eDelphi exercise and consensus voting were performed using Qualtrics survey software. Participants were adults with PG, healthcare professionals, researchers and industry representatives. RESULTS: Collaborative discussions and systematic reviews yielded 115 items, which were distilled into 15 prospective domains. The eDelphi exercise removed the three lowest-priority domains ('laboratory tests', 'treatment costs' and 'disease impact on family') and ranked 'pain', 'quality of life' and 'physical symptoms' as the highest-priority prospective domains. Consensus was reached on the domains of 'pain', 'quality of life' and 'clinical signs'. The domain of 'disease course/disease progression' narrowly failed to reach consensus for inclusion in the core set (32% of participants voted 'no'). Refinement of this domain definition will be required and presented for consideration at future consensus meetings. CONCLUSIONS: The UPGRADE core domain set for clinical trials in PG has been agreed by international multistakeholder consensus. Future work will develop and/or select outcome measurement instruments for these domains to establish a COS.

COVID-19 Infection in Hidradenitis Suppurativa Patients: A Retrospective Study.

Introduction: Hidradenitis suppurativa (HS) is associated with comorbidities that are risk factors for severe COVID-19 infection. We evaluated demographics and COVID-19 outcomes in HS patients. Methods: HS patients with COVID-19 (HS+/COVID+) and a randomized age-, race-, and sex-matched control population of patients without HS with COVID-19 (HS-/COVID+) were selected through a retrospective chart review. Data were collected on demographics, medications, comorbidities, vaccination status, and COVID-19 treatment/outcomes. Fisher's exact test was used to analyze the relationship between risk factors and COVID-19 outcomes. A p value of <0.05 was considered statistically significant. Results: There were 58 HS+/COVID+ patients, primarily African American (83%, n = 48) and female (88%, n = 51). Compared to HS+/COVID+ patients, HS-/COVID+ patients were significantly more likely to have cardiovascular disease (51% vs. 24%; p = 0.0029) and be pregnant (23% vs. 4%; p = 0.0093). HS+/COVID+ and HS-/COVID+ patients did not vary significantly in vaccination rate at time of COVID-19 diagnosis (6% vs. 5%; p = 0.78). HS-/COVID+ patients were significantly more likely to have COVID-19 complications (35% vs. 7%; p = 0.001) and receive COVID-19 treatment (37% vs. 7%; p = 0.0001) when compared to HS+/COVID+ patients. Conclusion: Our findings support the growing evidence that having HS itself may not be a risk factor for severe COVID-19 outcomes.

Low Rates of Psychosocial Screening and Lifestyle Counseling in Hidradenitis Suppurativa Patients in the USA.

Introduction: Although hidradenitis suppurativa (HS) is associated with psychosocial comorbidities such as depression as well as modifiable comorbidities such as obesity, rates of psychosocial screening and lifestyle counseling in the USA have not been characterized. Methods: This cross-sectional study utilized publicly available data from the National Ambulatory Medical Care Survey (NAMCS) between 2008 and 2018 to identify visits with a diagnosis of HS (ICD-9 code 705.83, ICD-10 code L73.2). T tests and multivariate logistic regressions analyzed trends in rates of screening and counseling while controlling for race, sex, and age. Survey weights are applied to each visit to represent a national sample. Results: Depression screening was completed in only 2% of reported visits. No visits reported screening for alcohol misuse, substance abuse, or domestic violence. There were low rates of counseling for weight reduction (7.8%), diet and nutrition (3.3%), exercise (2.4%), smoking (1.0%), and substance abuse (0.7%). Black patients and individuals with public health insurance received less screening and counseling overall. Conclusion: Rates of psychosocial screening and counseling on lifestyle modifications are low in ambulatory clinic visits for HS patients, and there are disparities based on race and insurance status. Implementing strategies to incorporate routine psychosocial screening and lifestyle counseling into visits may improve HS patient outcomes.

Single-cell RNA sequencing and spatial transcriptomics reveal cancer-associated fibroblasts in glioblastoma with protumoral effects.

Cancer-associated fibroblasts (CAFs) were presumed absent in glioblastoma given the lack of brain fibroblasts. Serial trypsinization of glioblastoma specimens yielded cells with CAF morphology and single-cell transcriptomic profiles based on their lack of copy number variations (CNVs) and elevated individual cell CAF probability scores derived from the expression of 9 CAF markers and absence of 5 markers from non-CAF stromal cells sharing features with CAFs. Cells without CNVs and with high CAF probability scores were identified in single-cell RNA-Seq of 12 patient glioblastomas. Pseudotime reconstruction revealed that immature CAFs evolved into subtypes, with mature CAFs expressing actin alpha 2, smooth muscle (ACTA2). Spatial transcriptomics from 16 patient glioblastomas confirmed CAF proximity to mesenchymal glioblastoma stem cells (GSCs), endothelial cells, and M2 macrophages. CAFs were chemotactically attracted to GSCs, and CAFs enriched GSCs. We created a resource of inferred crosstalk by mapping expression of receptors to their cognate ligands, identifying PDGF and TGF-ß as mediators of GSC effects on CAFs and osteopontin and HGF as mediators of CAF-induced GSC enrichment. CAFs induced M2 macrophage polarization by producing the extra domain A (EDA) fibronectin variant that binds macrophage TLR4. Supplementing GSC-derived xenografts with CAFs enhanced in vivo tumor growth. These findings are among the first to identify glioblastoma CAFs and their GSC interactions, making them an intriguing target.

Atopic Dermatitis: A Guide to Transitioning to Janus Kinase Inhibitors.

Janus kinase inhibitors (JAKis) are promising medications that the Food and Drug Administration recently approved for treatment of atopic dermatitis in January 2022. These medications offer a novel therapeutic mechanism and may be an additional treatment avenue for patients who are currently reliant on conventional immunosuppressants, such as cyclosporine A, methotrexate, or mycophenolate mofetil, or newer medications, such as dupilumab. However, redundant treatment puts patients at risk for excessive toxicity and polypharmacy, whereas abrupt tapering of a preexisting regimen may cause flares of the disease. Thus, transitioning to JAKis should be implemented strategically to retain the therapeutic benefit and minimize the risk of flares. Herein, we outline gradual transition schemas for patients needing to transition to JAKis from conventional immunosuppressants or dupilumab. There is no evidence-based guideline to instruct this transition to JAKis, and our recommendations are based on expert experience and the review of efficacy data from pivotal trials.

The "Understanding Pyoderma Gangrenosum, Review and Assessment of Disease Effects (UPGRADE)" Project: a protocol for the development of the core outcome domain set for trials in pyoderma gangrenosum.

INTRODUCTION: Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis that affects approximately 0.3-6 out of every 100,000 people worldwide. Clinical trials are scarce but there is growing interest in using newer and more targeted therapeutics to achieve disease remission. However, there are no standardized instruments to measure outcomes in PG and, therefore, future clinical trials are hampered by the absence of established and accurate means of assessment and comparison. Therefore, we aim to produce an internationally accepted core outcome set (COS) that will overcome this obstacle. This protocol outlines our intended approach to achieve the first part of this process, establishing a core outcome domain set. METHODS: An international team of PG stakeholders, consisting of physicians, wound care nurses, patients, scientists and industry representatives, has been assembled for the purpose of building a comprehensive and universally established set of core outcome domains. During the first step, we will generate items of relevance using a nominal process from all stakeholders. Items will be distilled and collapsed into potential domains and subdomains. A systematic review of current methods for reporting PG has already been published and domains identified in this work will be considered in the generation of the core domains set. During the second step, after the potential domains and subdomains are identified, stakeholders will participate in an e-Delphi exercise to rate the importance of (sub)domains. A final consensus meeting will be organized with the goal of establishing a core domain set. CONCLUSION: Pyoderma gangrenosum lacks an established COS and previously published clinical trials have used inconsistent measures established from similarly inconsistent domains. As a first step this study seeks to create a core domain set within the COS, to build the foundation for future core outcome work for PG.

Relationship Disturbances in Hidradenitis Suppurativa: A Patient Perspective.

Introduction: Hidradenitis suppurativa (HS) can significantly impact patients' relationships. Methods: Using an anonymous electronic survey, we aimed to determine what aspects of sexual relationships are affected by HS discomfort and patients' reluctance to discuss HS with their partner. Results: Among the 873 participants, 60.9% reported that some aspect of their relationship was affected by HS discomfort, with the greatest being their sexual encounters with spouse (49.1%). Furthermore, 43.0% (320) of participants reported feeling reluctant to discuss HS with their spouse/significant other, with the more common reason being fear of partner seeing boils and scars (84.7%). Multiple aspects of relationships can be affected by HS such as sexual encounters, overall relationship, and finding a relationship. Additionally, several communication barriers are present, such as fear of partner seeing boils and scars, partner thinking they had an infection such as a sexually transmitted disease, and fear of bloody or malodorous drainage, among others. The presence of anogenital pain, Hurley stage, gender, and age significantly affect these findings. Conclusion: Addressing HS-related relationship disturbances should be included in HS management.

Cutaneous Oxalosis Due to Primary Hyperoxaluria.

ABSTRACT: A 19-year-old girl presented to the emergency department with a progressively painful purpuric lesion on the left dorsal foot, which had initially appeared 2 days prior. Three months earlier, she had been diagnosed with end-stage renal disease. Her medical history also included recurrent urolithiasis for the past 5 years and liver failure. Biopsy revealed oxalate crystals occluding vessels with secondary epidermal and dermal ischemia. Oxalate crystals were also visualized in the vessel walls and free in the subcutis. Genetic testing confirmed the diagnosis of primary hyperoxaluria type 1. She was treated with sodium thiosulfate, apixaban, pentoxifylline, wound care, and palliative care. At 4-month follow-up, the cutaneous manifestations of oxalosis were confined to only her feet, and she was undergoing evaluation for combined liver and kidney transplant. Cutaneous oxalosis because of primary hyperoxaluria should be considered in young patients presenting with purpuric lesions, recurrent urolithiasis, and early-onset renal failure.

Guidance on COVID-19 Vaccination in Hidradenitis Suppurativa Patients: A Modified Delphi Consensus of Experts.

Introduction: Hidradenitis suppurativa (HS) patients may be at increased risk of COVID-19 infection and complications from their medications and comorbidities. There is a lack of expert consensus on recommendations for the COVID-19 vaccine for HS patients. Herein, we aim to provide expert-driven consensus recommendations regarding COVID-19 vaccinations in HS patients. Methods: A modified Delphi consensus survey developed by a core committee of 7 dermatologist HS experts consisting of 4 demographic questions and 12 practice statements was distributed to the US HS Foundation-sponsored provider listserv. Participants were attending physician HS experts. Survey results were to be reviewed by the core group and revised and resubmitted until consensus (≥70% agreement) was achieved. Results: Among the 33 survey participants, there were 30 (87%) dermatologists, 1 general surgeon, 1 plastic surgeon, and 1 rheumatologist. Consensus for all 12 statements on vaccine counseling and HS treatment counseling was achieved after the first round. Discussion/Conclusion: For now, this consensus can serve as a resource for clinicians discussing COVID-19 vaccination with their HS patients. These recommendations will need to be updated as new evidence on COVID-19 emerges.

Allergen Composition, Marketing Claims, and Affordability of Pediatric Sunscreens.

BACKGROUND: Childhood sun exposure is associated with development of future skin cancers. Sunscreens are an important tool to prevent harmful ultraviolet rays. OBJECTIVES: The aims of the study are to evaluate sunscreens targeted to children and to analyze cost, marketing claims, ingredients, and allergens to help consumers select products. METHODS: The top 50 pediatric sunscreens across retailers were analyzed for their cost, marketing claims, ingredients, vehicles, and containers. Ingredients were compared with the American Contact Dermatology Society 2020 Core Allergen List. RESULTS: The mean price was $6.20 per ounce (range, $0.25-$39.98). The mean sun protection factor was 48.5 (range, 30-100; SD, 48.5). There was a mean of 17.5 ingredients and a mean of 1.1 allergens in products. On average, products marketed as "sensitive skin" were not only significantly more expensive ($8.90 vs $3.50 per ounce, P = 0.01) but also were significantly more likely to not contain any allergens (36.0%, n = 18 vs 12%, n = 6; P = 0.05). Products with mineral-only UV blockers were significantly less likely to have any allergen when compared with products that had chemical UV blockers (5.6%, n = 1 vs 94.4%, n = 17; P = 0.02). CONCLUSIONS: The current market of pediatric sunscreens varies significantly in price, marketing claims, and active ingredients. Products marked as suitable for sensitive skin had significantly fewer allergens, but a majority of these products still had at least one allergen. Many sunscreens contain contact allergens, which is an important selection consideration.

Characterization of Legal Claims Involving Patients with Pyoderma Gangrenosum.

OBJECTIVE: To review the litigation literature related to patients with pyoderma gangrenosum (PG) to characterize the legal issues they face. DATA SOURCES: Data sources include law databases Casetext and Lexis Nexis. STUDY SELECTION: All disability and medical liability claims directly involving patients with PG were included. DATA EXTRACTION: Data extraction came directly from Casetext and Lexis Nexis. All cases extracted came from September 1965 to December 2020. This resulted in 32 cases, 18 of which were excluded because they did not mention the plaintiff having a diagnosis of PG (n = 14). DATA SYNTHESIS: The review found a total of six medical liability cases in which adverse health outcomes were reported, including prolonged suffering (2/6 cases), unnecessary treatments or procedures (2/6), exacerbation of disease (1/6 cases), and permanent scarring (1/6 cases). Despite this, two plaintiffs won their case and only one of them received any monetary award. Similarly, of the eight disability claims in the review, four were ruled in the favor of the plaintiffs and only two resulted in immediate awarding of benefits. Half of medical liability cases occurred in correctional facilities after the denial of appropriate care. CONCLUSIONS: The findings demonstrate a need for access to specialty care in incarcerated populations. Cases that occurred in a hospital setting also stress the importance of initiatives such as telemedicine to efficiently increase access to care in a cost-effective manner. Further, PG has been recognized as a severe impairment in disability claims despite patients being denied because they were deemed able to perform other work.

Discordant Timing of Hypoglycemic Agent Screening Causing Delayed Diagnosis of Sulfonylurea-Induced Hypoglycemia.

Background: Oral hypoglycemic agents are a frequent cause of hypoglycemia in nondiabetic people. Here, we report a case of recurrent hypoglycemia caused by glipizide, in which diagnosis was delayed because of a combination of delayed hypoglycemic agent screening and low sensitivity of the hypoglycemic agent screening panel used. Case Report: A 66-year-old woman repeatedly presented with symptomatic hypoglycemia. At the first presentation, the serum glucose level was 40 mg/dL (2.2 mmol/L), C-peptide level was 13.1 ng/mL (0.8-3.1 ng/mL), proinsulin level was 96.9 pmol/L (<18.8 pmol/L), and insulin level was 164 mU/L (<17 mU/L). An initial hypoglycemic agent screening, performed 24 hours after admission, yielded a negative result, leading to prolonged and recurrent hospitalizations for workup and localization of insulinoma. A hypoglycemic agent screening at a subsequent presentation, concordant with hypoglycemia, yielded a positive result for glipizide, which was at a level of 320 ng/mL (reporting limit, 40 ng/mL). An examination of the patient's home medications revealed a container, labeled as benztropine, containing glipizide tablets. After the diagnosis of glipizide-induced hypoglycemia, the patient had no further episodes of hypoglycemia. Discussion: The failure to detect glipizide using the initial hypoglycemia agent assay was likely because of a combination of a delay in the initial screening and low sensitivity of the assay for glipizide compared with that of other available assays. Here, we discuss important considerations for the interpretation of hypoglycemic agent screening in the diagnosis of hypoglycemia, including the timing of collection and reporting, pharmacokinetics of culprit agents, and sensitivity of the hypoglycemic agent panel used. Conclusion: Screening tests for hypoglycemic agents are necessary for the evaluation of hypoglycemia because their biochemical evaluation may be indistinguishable from that of insulinoma.

A review of IL-36: an emerging therapeutic target for inflammatory dermatoses.

BACKGROUND: IL-36 cytokines are members of the IL-1 superfamily. Increasing evidence in the IL-36 pathway demonstrates their potential as a therapeutic target for treating inflammatory skin diseases, such as generalized pustular psoriasis (GPP). OBJECTIVE: A narrative review was written to further study preclinical and clinical evidence for the role of IL-36 in psoriasis, atopic dermatitis (AD), hidradenitis suppurativa (HS), acne, autoimmune blistering diseases, and neutrophilic dermatoses. RESULTS: IL-36 has important downstream effects such as inducing expression of inflammatory cytokines, antimicrobial peptides, and growth factors. Increased expression of IL-36 cytokines has been observed in the lesional skin of patients with psoriasis. Studies of other inflammatory skin diseases have also noted similar findings, albeit to a lesser extent. IL-36 inhibition has been shown to be effective in GPP and is currently being studied for other inflammatory skin diseases. CONCLUSIONS: The IL-36 pathway contributes to pathogenesis of many inflammatory skin diseases and is a promising therapeutic target.

Calciphylaxis: Part I. Diagnosis and pathology.

Calciphylaxis is an uncommon but devastating disorder characterized by vascular calcification and subsequent cutaneous tissue necrosis. This results in exquisitely painful and slow healing wounds that portend exceptionally high morbidity and mortality. The diagnosis of this condition can be complicated because there are no conclusive serologic, radiographic or visual signs that this disease is manifesting. The differential of tissue necrosis is broad, and identifying calciphylaxis requires an adroit understanding of the risk factors and physical signs that should raise suspicion of this condition. Reviews on this subject are uncommon and lack directed commentary from disease experts on the best diagnostic approach for patients suffering from this disease. The goal of this article is to update practicing dermatologists on the current standard of care for calciphylaxis.

Calciphylaxis: Treatment and outlook-CME part II.

Calciphylaxis is a rare and devastating condition with important systemic ramifications. This second-part of our CME aims to educate the practicing dermatologist on the current standard of care once a diagnosis of calciphylaxis is confirmed or highly suspected. The key pathologic findings, as well as the role and limitations of biopsy, are reviewed. We aim to guide readers through the complex hospitalization and posthospitalization management of these medically vulnerable patients. Collaboration with other specialists will be discussed. Experimental and developing treatments are discussed, and the outlook of the condition is reported.